Kindlin-3 Is Essential for the Resting α4ß1 Integrin-mediated Firm Cell Adhesion under Shear Flow Conditions.
J Biol Chem
; 291(19): 10363-71, 2016 May 06.
Article
em En
| MEDLINE
| ID: mdl-26994136
ABSTRACT
Integrin-mediated rolling and firm cell adhesion are two critical steps in leukocyte trafficking. Integrin α4ß1 mediates a mixture of rolling and firm cell adhesion on vascular cell adhesion molecule-1 (VCAM-1) when in its resting state but only supports firm cell adhesion upon activation. The transition from rolling to firm cell adhesion is controlled by integrin activation. Kindlin-3 has been shown to bind to integrin ß tails and trigger integrin activation via inside-out signaling. However, the role of kindlin-3 in regulating resting α4ß1-mediated cell adhesion is not well characterized. Herein we demonstrate that kindlin-3 was required for the resting α4ß1-mediated firm cell adhesion but not rolling adhesion. Knockdown of kindlin-3 significantly decreased the binding of kindlin-3 to ß1 and down-regulated the binding affinity of the resting α4ß1 to soluble VCAM-1. Notably, it converted the resting α4ß1-mediated firm cell adhesion to rolling adhesion on VCAM-1 substrates, increased cell rolling velocity, and impaired the stability of cell adhesion. By contrast, firm cell adhesion mediated by Mn(2+)-activated α4ß1 was barely affected by knockdown of kindlin-3. Structurally, lack of kindlin-3 led to a more bent conformation of the resting α4ß1. Thus, kindlin-3 plays an important role in maintaining a proper conformation of the resting α4ß1 to mediate both rolling and firm cell adhesion. Defective kindlin-3 binding to the resting α4ß1 leads to a transition from firm to rolling cell adhesion on VCAM-1, implying its potential role in regulating the transition between integrin-mediated rolling and firm cell adhesion.
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Integrina alfa4beta1
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Proteínas de Membrana
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Proteínas de Neoplasias
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2016
Tipo de documento:
Article